9alpha-difluoromethyl and 9alpha-trifluoromethyl pregnenes



United States Patent 3,409,610 9a-DIFLUOROMETHYL AND 9oc-TRIFLUOR0- METHYL PREGNENES John H. Fried, Palo Alto, Calif., assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed June 27, 1966, Ser. No. 560,864 21 Claims. (Cl. 260-2395) In the above formulas, X represents difluoromethyl or trifluoromethyl; Y represents hydrogen or fiuoro; Z represents a saturated bond or an ethylenically unsaturated bond between C-1 and C-2; R represents C=O or AcO wherein R" represents hydroxy, a carboxylic acyloxy group of less than 12 carbon atoms, tetrahydropyran-Z- yloxy or tetrahydrofuran-Z-yloxy; R represents C=O or R represents hydroxy or a carboxylic acyloxy group'of less than 12 carbon atoms; R represents hydrogen, fiuor-o or methyl; R represents hydrogen, hydroxy or a carboxylic acyloxy group of less than 12 carbon atoms; R represents hydrogen, alpha hydroxy, alpha methyl or beta methyl; R and R together represent the group at the 16a,17a-position wherein each of R and R represent hydrogen or a hydrocarbon group of up to 8 carbon atoms; and R represents hydrogen, phenyl, chlorophenyl, fluorophenyl, methoxyphenyl and methylphenyl, provided that When R represents alpha hydroxy that R represents hydroxy or a carboxylic acyloxy group of less than 12 carbon atoms.

The novel compounds of the present invention of the above formulas are valuable pharmacological agents having anti-flammatory and other desirable corticoid activities. They are administered in the usual pharmaceutical forms.

The carboxylic acyl or acyloxy groups of the compounds of the present invention contain less than 12 carbon atoms and may be of a straight, branched, cyclic 0r cyclic-aliphatic chain structure. This structure may be saturated, unsaturated, or aromatic and optionally substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like; Typical esters thus include acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, fi-chloropropionate, adamantoate, and the like.

Compounds of the present invention embraced by Formula A can be prepared according to the following illustrated process.

BMD

From l II From 1 I BMD VII

BMD

XI In the above formulas, R represents hydrogen, alpha methyl or beta methyl, Ac is an acyl group of a hydrocarbon carboxylic acid of less than 12 carbon atoms, preferably acetyl, and BMD is the side chain protecting group 17a,20;20,2l-bismethylenedioxy.

In practicing the above process for the preparation of the novel 9ot-difluoromethy1 derivatives (VI), i.e. the reaction sequence I-II-III-IVVVI, the starting material I is reacted with an alkali metal salt of chlorodifluoro acetic acid, e.g. sodium chlorodifluoroacetate, in an inert organic solvent, e.g. a glycol ether, to furnish the corresponding 9a,11a-difluoromethylene steroid 11 which upon treatment with a strong base, e.g. potassium hydroxide, in aqueous organic solvent such as an aqueous lower monohydric alcohol furnishes the '9a-difluoromethyl steroid III. Oxidation of the steroid III as by treatment with, for example, chromium trioxide in pyridine furnishes the 3-keto derivative IV which is then converted into the 3-keto-A steroid V by treatment with bromine and lithium chloride as described in detail hereinafter. Treatment of the steroid V with an acid, for example, aqueous formic acid, hydrofluoric acid, hydrochloric acid, and the like furnishes the 9a-difluoromethyl cortisone VI or alter natively the 16a-methyl or 165-methy1 derivative thereof (VI, R'=a-CH or B-CHg) depending upon the starting material.

In practicing the above process for the preparation of the novel 9a-trifiuoromethy1 cortisones XI of the present invention, i.e. the reaction sequence IVIIVIII-IX-X- XI, the starting material I is treated with trifluoroiodomethane in the presence of a catalyst such as an organic peroxide or ultraviolet light to furnish the 9a-trifluoromethyl steroid VII. By subjecting the steroid VII to the procedure described hereinabove for the conversion of II-III-IV-V-VI, there is obtained the novel 9a-trifluoromethyl cortisones XI.

The starting material I can be obtained according to the following outlined process wherein Ac, BMD and R are as defined hereinabove.

CiH 0A: CH 0 In practicing the above process, the starting compound XII is hydrolyzed as by treatment with a base in a lower alcohol to obtain the corresponding 2l-hydroxy compound XIII. By treatment of the compound XIII with formaldehyde in the presence of hydrochloric acid the protecting group 17a,20;20,2l-bismethylenedioxy is in troduced to furnish the compound XIV which is then acylated at C-3 as by treatment with a hydrocarbon carboxylic anhydride, e.g. acetic anhydride in pyridine, to provide the 3a-acyloxy compound XV. Treatment of the compound XV with bromine in chloroform in the presence of a small amount of hydrogen bromide furnishes the 9a-bromo compound XVI which upon treatment with lithium in liquid ammonia followed by treatment with acetyl chloride furnishes the enol acetate 1.

Compounds of the present invention according to Formulas VI and XI can be converted into the corresponding 1(2)-dehydro derivative by refluxing with selenium dioxide or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in, e.g., dioxane. This thus-obtained A -derivatives can be further dehydrogenated as by refluxing with chloranil in tertiary butanol to obtain the C6,7-dehydro derivative i.e. a A -triene. Alternatively, the dehydrogenation at C-6,7 may be effected prior to the dehydrogenation at C-1,2 to obtain the A -diene derivatives of Formulas VI and XI.

The novel 9a-difluoromethyl and 9a-trifluoromethyl cortisones of the present invention and the corresponding C-l,2 and C6,7 dehydro derivatives can be converted into the corresponding 3/3-hydroxy and/or lLB-hydroxy derivative according to the following outlined process.

In the above formulas X, R, defined hereinabove and Z XVIII as by treatment with sodium borohydride inan organic solvent which is thereafter selectively oxidized at 0-3 by treatment with, for example, manganese dioxide and tetrahydrofuran to obtain the 3-keto derivative 6 XIX. The 3-keto steroid XIX is then subjected to acid hydrolysis as by treatment with formic acid, acetic acid, hydrofluoric acid, or the like to remove the bisrnethylenedioxy side chain protecting group to form the steroid XX. The steroid XX is then esterified at C2l as by treatment with for example, acetic anhydride in pyridine to obtain the corresponding 2l-acylate XXI. Selective reduction of the steroid XXI at C-3 as by treatment with, e.g., lithium aluminum t-butoxide inan organic solvent, for example, te-trahydrofuran, furnishes the 3 8,

ILB-diol XXII. The 2l-ester group of the steroid XXII may be subjected to hydrolysis as, for example by treatment with a base in an aqueous organic solvent to obtain the corresponding'fre'e 2l-alcohol'. M

In practicing the 'above process, dehydrogenation at -l,2 and/or C6,7 may be performed before or after carrying out the described tives may be prepared in the manner described hereinabove.

,The 3fl-acylate or 3fl-ether derivatives of the 9a-trifluoromethyl and 9a-difluoromethyl compounds of the present invention can be obtained byconventional acyla; tion and etherification methods known in the art. Thus, treatment of the steroid XXII with, for example, a carboxylic anhydride or an acyl chloride in an organic solvent, e.g. pyridine furnishes the corresponding 3 3-acylate, e.g. the E s-acetate. Alternatively, treatment of steroid XXII with dihydropyran or dihydrofuran in the presence of, e.g., para-toluenesulfonyl chloride furnishes the corresponding SB-tetrahydropyran-Z-yl ether or 3fi-tetrahy drofuran-3-yl ether. Thereafter, if desired, the llfi-hydroxy group may be oxidized as by treatment with manganese dioxide or 2,3-dichloro-5,6-dicyano-1,4-benzoqui none in tetrahydrofuran to obtain the ll-keto derivative. Preferably, the lip-hydroxy substituent is converted into the ll-oxo before removal of the acylate at (3-21. The 2l-acylate group may be removed after oxidation at C-1 1, if desired, by hydrolysis with, e.g., potassium hydroxide in an aqueous alcohol to obtain the free 2l-alcohol.

The compounds of the present invention having an alpha hydroxy group at C-16, i.e. compounds according to, for example, Formula A wherein R is alpha hydroxy and R is hydroxy or acyloxy are obtained by incubating the C-l6 unsubstituted compounds with Streptomyces roseochromogenus as hereinafter set forth in detail.

The compounds of the present invention having an esprocedure. The dehydro deriva ter group at C-17 are prepared from a 17a,21-diol derivative of the present invention as outlined below.

In the above formulas, X, R R Z and Z are as defined hereinabove and R is hydrogen or a lower alkyl hydrocarbon group of less than 10 carbon atoms.

In practicing the above outlined process, the 170:,21- diol XXIII is treated with a lower alkyl ortho ester, e.g. methylorthovalerate, methylorthocaproate, methylorthoacetate, and the like to obtain the ortho ester XXIV. The ortho ester upon treatment with acid, e.g. hydrochloric acid, in an aqueous organic solvent at a temperature of from room temperature to reflux temperature furnishes the 17u-acylate XXV.

The 6a-methyl derivatives of the 9a-difluoromethyl and 9a-trifiuoromethyl corticoids of the present invention are obtained according to the following outlined process.

BMD sun 0 O XXVI ZBMD o XXIX H0 xxvrrr nun sun HO JQDC mm no 5 5 H acorn: i 0 xxxrr i 3 3 cn orr XXXVIII In the above formulas X, R Ac and BMD are as defined hereinabove.

In practicing the above outlined process the starting material XXVI is converted into the enol acetate XXVII as by treatment with acetic anhydride and acetyl chloride at reflux temperatures. The enol acetate XXVII is then reduced as by treatment with sodium borohydride in aqueous organic solution as set forth in detail hereinafter to obtain the A -3B,llfi-dio1 steroid XXVIII which is converted into the 5a,6ot-oxido steroid XXIX as by treatment with, tor example, monoperphthalic acid in ether at room temperature for several hours. The steroid XXIX is then converted into the 5a-hydroxy-6-methy1 steroid XXX as by treatment with methyl magnesium bromide in ether, and is then oxidized by treatment with chromium trioxide in sulfuric acid to yield the steroid XXXI. The A -6a-methyl steroid XXXII is obtained from the Soc-hydroxy-6-methyl steroid XXXI as by treatment with an alkali hydroxide, eg sodium hydroxide, and organic solvents such as methanol. Reduction of the steroid XXXII as by treatment with sodium borohydride rurnishes the 313,1118-di0l steroid XXXIII which is selectively oxidized as by treatment with, for example, manganese dioxide in an organic solvent to yield the steroid XXXIV. The side chain protecting group, i.e. bismethylenedioxy is removed by treatment with acid as described hereinbefore, for example, aqueous hydrofluoric acid to furnish the steroid XXXV. The steroid XXXV is then acylated as by treatment with acetic anhydride and acetic acid to furnish the corresponding 21-acylate XXXVI which is then subjected to oxidation, e.g. manganese dioxide, and the like, to obtain the ll-oxo substituted steroid XXXVII. The steroid XXXVII is then subjected to saponification as by treatment with for example potassium hydroxide in aqueous methanol to furnish the corresponding 21-hydroxy steroid XXXVIII.

The compounds prepared by the above-described proc- 9 ess, particularly, compounds represented by Formulas XXXII through XXXVIII may be subjected to dehydrogenation at positions C1, 2 and C6, 7 in the manner described hereinabove to obtain the A A, A unsaturated derivatives thereof.

The novel compounds of this invention having a 16 17a-acetal or 16a,17a-ktal group are obtained by treatment of a l6a,17a-dio1 derivative of the present invention with a ketone or an aldehyde under anhydrous conditions and in the presence of a catalyst such as copper sulfate, dry hydrogen chloride, or perchloric acid without using a solvent or in the presence of a solvent inert to the reaction, such as dioxane, tetrahydrofuran, and the like. The conversion of a 16a,17a-dl01 derivative of the present invention into a l6u,l7a-acetal or ketal may be shown as follows using for the purposes of illustration only the preparation of a l6a,l7ot-acetal or ketal embraced by Formula A above.

In the above formulas, R R R R, R and Z are as defined hereinabove.

The acetals and ketals of the present invention exemplified by Formula XL may be considered as 16u,17ot methylenedioxy compounds wherein the methylenedioxy group is bound with its oxygens to positions (1-160; and

17oz of the steroid and'wherein one or both hydrogen atoms of the methylenedioxy group may be substituted with the residue of a hydrocarbon of up to 8 carbon atoms, saturated or unsaturated, of straight or branched chain, cyclic or of a chain combining these moieties.

Compounds having a fluoro group at C6 are obtained from a C6 unsubstituted derivative of the present invention. A fiuoro group is introduced at C6, preferably before other derivatives are made such as the C-l,2 and C6,7-dehydro derivatives, 16a-hydroxy, and the 1604,1711- alkylidenedioxy compounds. A process for the preparation of the 6-fluoro derivatives of this invention may be illustrated as follows.

In the above formulas, R R R R R and X are as defined hereinabove.

In practicing the above process, the 3-keto-A starting material XLI is converted into the enol ether XLII as by treatment with ethylorthoformate in the presence of an acid catalyst such as p-toluenesulfonic acid. Treatment of the enol ether with, e.g., perchloryl fluoride in an organic solvent furnishes a mixture of the 6a-fluoro and 6,8-fiuoro derivative which may be separated by chromatography or alternatively, the mixture of isomers may be treated with hydrogen chloride in acetic acid to furnish the fi a-fluoro compound XLIII which may then be subjected to dehydrogenation at C1,2 and C6,7, in the manner described hereinabove to obtain the corresponding diene and triene derivatives. Thereafter, hydrox'y, ester and ether derivatives may be prepared according to the procedure de scribed hereinabove.

The novel 9u-difluoromethyl and 9m-trifiuorornethyl compounds of the present invention according to Formula C having a 6ix,7a-difluoromethylene group or a 611,70:- methylene group are obtained from a C6,7 dehydro derivative of the present invention. These compounds may be prepared according to a process illustrated as follows.

BMD

wherein R R R X and Y are as defined hereinabove.

In practicing the above illustrated process, the A starting material XLIV is treated with sodium difluoroacetate in an inert solvent to furnish the 6a,7a-difiuoromethylene steroid XLV (XLV; Y=fluoro). Alternatively, the reaction of steroid XLIV with dimethylsulfoxonium methylide in dimethylsulfoxide furnishes the 6a,7amethylene steroid XLV (XLV, Y=hydrogen). The 170:, 20;2 0,2l-bismethylenedioxy protecting group is thereafter removed by treatment with aqueous acid to furnish the steroid XLVI which may then be reduced to obtain a free hydroxy group at C-3, if desired. The steroid XLVI may also be acylated at 0-21, Cl7 and C-3 in accordance with the procedure described hereinabove and an ether group introduced at C3, if desired. Steroid XLVI may also be dehydrogenated at C-1,2 to obtain the 1,2- dehydroderivative by treatment with, e.g. selenium dioxide.

The pyrazole derivatives of the novel 9a-difluoromethyl and 9a-trifluoromethyl compounds or Formulas 'D, E and F are prepared, at outlined below, through the treatment of a 2-hydroxymethylene-3-keto-A or A derivative of the invention with a hydrazine of the formula NH NHR wherein R represents hydrogen, phenyl, chlorophenyl, fluorophenyl, methoxyphenyl, or methylphenyl. The steroid side chain is preferably protected during this conversion as through esterification or through formation of the bismethylenedioxy protecting group.

In the above formulas, R defined hereinabove. R is hydrogen, having alpha configuration when Z The compounds according to Fonmula XLIX have R R Z and X are as methyl or fiuoro, R is a saturated bond.

anti-fiammatory and other desirable corticoid activity. They may be acylated at C-2l and/or (3-17, if desired, via the procedure described hereinabove.

In lieu of using a A -ene or a A -diene starting material illustrated by Formula XLVII, a 3-keto-A -6a,7a-difiuoromethylene or ufla-methylene derivative can be used in the above described process to obtain the pyrazole compounds of Formula F.

The novel 9a-trifiuoromethyland 9a-difluoromethyl compounds of the present invention wherein R is hydrogen are prepared from the corresponding 9a-trifioromethyl-17wacyloxy and 9a-difluoromethyl-17a-acyloxy compounds of this invention, preferably acetoxy, by treatment with chromous chloride or zinc in acetic acid as described in detail hereinafter. The reaction can be illus trated as follows.

In the above formulas, R, R R R R, as defined hereinabove.

The above compounds represented by Formula Ll-I can be converted into the 9*a-trifluoromethyland 9u-difluoromethylpyrazoles by the procedure described hereinabove. These compounds can also be transformed into the 606,70:- difluoromethylene and 6a,7a-methylene derivatives by the procedure described hereinabove. In the foregoing transformation, and for the preparation of other derivatives of the present invention as described hereinabove, the side chain can be protected by ketalization as for example, by refluxing with an alkylene glycol preferably ethylene glycol, in benzene in the presence of para-toluenesulfonic acid for a period of time of the order of about 12 hours or more. The side chain protecting group can thereafter be removed by treatment with acid in'an organic solvent, e.g. para-toluenesulfonic acid in acetone and the like.

The following examples serve to illustrate but are not intended to limit the scope of the present invention.

PREPARATION A One gram of 3a,17a,2l-trihydroxy-SB-pregnane-11,20- dione-21-acetate is allowed to stand at room temperature in a nitrogen atmosphere for 5 hours with 1 g. of potassium bicarbonate in 1 0 ml. of water and 90 ml. of methanol. At the end of this time the reaction mixture is neutralized with acetic acid, the methanol is evaporated under Z and Z reduced pressure and the residue is extracted with ethyl acetate and water. Evaporation of the ethyl acetate from these extracts yields 3a,l7a,2l-trihydroxy-5fl-pregnane 11,20-dione which is collected by filtration and recrystallized from acetonezhexane.

To a solution of 5 g. of the above 3a,17a,21-trihydroxy compound in 200 ml. of chloroform are added 40 ml. of 37% aqueous formaldehyde and 5 ml. of concentrated hydrochloric acid. The mixture is stirred for 48 hours at room temperature and the two layers then separated. The aqueous layer is extracted with chloroform and the combined organic layer and chloroform extracts are washed with water to neutrality, dried over sodium sulfate and evaporated to dryness to yield 17a,20;20,2l-bismethylenedioxy-3a-hydroxy-5p3-pregnan-ll-one which is recrystallized from methanolaether.

A mixture of 1 g. of the above 17a,20;20',21:bismethylenedioxy-3u-hydroxy compound, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 17a,2(); 20,21 bismethylenedioxy 3a acetoxy 55 pregnan- 1l-0ne which may be further purified through recrystallization from acetonezhexane.

To a stirred solution of 1 gram of 17a,20;20,21- bismethylenedioxy 30c acetoxy 55 pregnan 11- one in 40 ml. of dioxane is added in a dropwise fashion a solution containing 1.2 molar equivalents of bromine in dioxane at a temperature of about 15 C. A few drops of anhydrous hydrobromic acid solution in chloroform are then added and the mixture is allowed to stand at room temperature for about 30 minutes. Then, the mixture is poured into 5% aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform extracts are washed with water, dried and evaporated under reduced pressure to yield 17a,20;20,2l-bismethylenedioxy-3a-acetoxy-9a-brOmo-SB- regnan-ll-one which is further purified through recrystallization from methylene chloridezhexane.

To a mixture of 2 g. of the above 9a-bromo compound, 30 ml. of anhydrous tetrahydrofuran, and 50 ml. of anhydrous liquid ammonia, there is slowly added 3 molar equivalents of metallic lithium based on the steroid starting material with stirring and while maintaining the temperature at about to C. After the addition of lithium is completed, the mixture is stirred for about 30 minutes and then 3 molar equivalents of acetyl chloride and tetrahydrofuran is slowly added. The reaction mixture is then left standing for about /2 hour after the addition of acetyl chloride is completed. Thereafter, the liquid ammonia is allowed to evaporate and the reaction mixture is then diluted with methylene chloride, poured into water and separated. The organic phase is washed with water, dried and evaporated to dryness to yield 17a, 20;20,21-bismethylenedioxy-3a,ll diacetoxy 5fi-pregn-9 (ll)-ene which may be purified by chromatography or fractional crystallization from acetonezhexane.

Example 1 To a gently refluxing and stirred-solution of 1 gram of 17a,20;20,21 bismethylenedioxy 311,11 diacetoxy 5,8- pregn-9(1l)-ene in 8 ml. of dimethyl diethylene glycol ether, there is added in a dropwise fashion over a two hour period a solution of 30 equivalents of sodium chlorodifluoroacetate in 30 ml. of dimethyl diethylene glycol ether. Refluxing is continued until the reaction is complete, as indicated by the UV. spectra, and the'mixture is then filtered. The filtrate is then evaporated to'dryness under reduced pressure and the residue chromatographed with methylene chloride on alumina to yield 17a,20;20,21- bismethylenedioxy-3 a,1l,6 diacetoxy 9u,lla difluoromethylene-Sfi-pregnane.

By repeating the above process using as the starting material, the corresponding 16a-methyl and 16,8-methyl compounds of 17a,20;20,2l-bismethylenedioxy 3 x,l1 diacetoxy-S B-pregn-9(l1)-ene, there are obtained the corresponding 16x-methyl and 16,8-methyl derivatives of 170:, 20;20,2l-bismethylenedioxy 30,llB-di21CGtOXY-9oc,1lot-difluoromethylene-Sfi-pregnane.

Example 2 A solution of 1 g. of 17a,20;20,2l-bismethylenedioxy- 3a,11/3-diacetoxy-9a,1la-difluoromethylene Sfi-pregnane in 50 ml. of methanol is heated at reflux for 3 hours with a solution of .2 g. of potassium hydroxide in 1 ml. of water. The reaction mixture is then poured into ice water and the solid which forms collected by filtration, washed with water to neutrality and dried to yield 17a,20;20,21 bismethylenedioxy-3a-hydroxy 9a difluoromethyl 5,8- pregnan-ll-one which is recrystallized from methylene chloridezether.

A solution of 6 g. of 17a,20;20,2l-bismethylenedioxy- 3a-hydroxy-9a-difiuoromethyl-Sfi-pregnan ll-one in 120 ml. of pyridine is added to a mixture of 6 g. of chromium trioxide in 20 ml. of pyridine. The reaction mixture is allowed to stand at room temperature for 15 hours, diluted with ethyl acetate and filtered through Celite diatomaceous earth. The filtrate is washed well with water, dried and evaporated to dryness to yield 17a,20;20,2l-bismethylenedioxy-9a-difluoromethyl 55 pregnane-3,11-dione which may be further purified by recrystallization from acetone: hexane.

To a stirred solution of 1 g. of the thus-obtained 3,11- dione in 17 ml. of chloroform and 20 ml. of glacial acetic acid, cooled to -10 C. are added a few drops of a solution of hydrogen bromide in acetic acid followed by a solution of 0.46 g. of bromine in 12 ml. of chloroform, the latter at such a rate that the reaction'mixture maintains'a pale yellow color. A cold solution of 2.5 g. of sodium acetate in 17 ml. of water is then added. The layers are separated and the aqueous layer is extracted with chloroform. The combined extracts and organic layer are washed with water, dilute potassium bicarbonate solution and with water, dried over sodium sulfate and evaporated to dryness to yield the 4-bromo intermediate, 1 g. of which is dissolved in 20 ml. of dimethylformamide containing 0.5 g. of lithium chloride. This solution is stirred under nitrogen at steam bath temperatures for four hours. After cooling to 10 C., 11 ml. of water are added with stirring at such a rate that the temperature is maintained below 30 C. Stirring in an ice bath is continued until solid forms and this material is then collected by filtration, washed with cold 1:1 water:dimethylformamide and then water and dried to yield l7a,20; 20,21-bismethylenedioxy-9a-difluoromethylpregn-4-ene-3,ll-dione which is further purified through recrystallization from acetone with charcoal decolorization as necessary.

One gram of the thus-obtained compound in 100 ml. of 80% acetic acid is held under nitrogen for 7 hours at 90. The mixture is then concentrated under vacuum to a small volume and poured into water. The solid which forms is collected by filtration washed well with water, dried and recrystallized from acetonezhexane to yield 90:-

1 4 dilluoromethyl-l7ot,2l-dihydroxypregn 4-ene-3,ll,20-trione.

By using the 16a-methyl and 16fi-methyl substituted compounds obtained by the method of Example 1 as the starting material in the process of this example, there are obtained 9a-difluoromethyl-l6a-methyl-17u,2l-dihydroxypregn-4-ene 3,11,20 trione and 90a difiuoromethyl-lGflmethyl-17a,2l-dihydroxypregn-4-ene 3,11,20 trione, respectively.

Example 3 A mixture of 5 g. of 17a,20;20,2l-bismethylenedioxy- 3u,11-diacetoxy-5fi-pregn-9(11)-ene, 2.5 ml. of anhydrous pyridine and 10 ml. of trifluoroiodomethane is irradiated with ultra-violet light from a high-pressure quartz-mercury lam-p (Philips Type 93110 E) at a distance of 4 cm. dur ing 72 hrs. in a sealed and cooled quartz tube. Thereafter the trifluoroiodomethane is distilled off and the residue is treated with 75 ml. of ether. The precipitate thereby formed is filtered 01f, and the filtrate is washed with 2X10 ml. of l-N hydrochloric acid, thereafter with a saturated solution of NaHCO and subsequently with water. After drying over MgSO a few drops of pyridine are added and thereafter the solution is evaporated to dryness. The residue is recrystallized from methanol containing 0.5% pyridine to yield 17u,20;20,21-bismelthylenedioxy-3 a-acetoxy-9a-trifluoromethyl-5fi-pregnan-1 l-one.

Similarly, by using the corresponding 16a-methyl or 16B-methyl derivative of l7a,20;20,2l-bismethylenedioxy- 311,11-diacetoxy-5/3-pregn-9(l1)-ene as the starting material in the process of this example, there is obtained 17a, 20;20,2l-bismethylenedioxy c trifiuoromethyl 16mmethyl-3a-acetoxy-5/3 pregnan-ll-one and 17a,20;20,2lbismethylenedioxy-9a-ltrifluoromethyl methyl-3aacetoxy-S/i-pregnan-l l-one.

Example 4 The method of Example 2 is repeated with the exception of using l7a,20;20,20-bismethylenedioxy-3a-acetoxy- 9a-trifiuoromethyl-Sfl-pregnan-1l-one in lieu of 1711,20; 20,2l-bismethylenedioxy 3ot,11fi diacetoxy 9a,11a-difluoromethylene-Sfi-pregnane as the starting material to furnish 9a-tril'luoromethyl-17a,2l-dihydroxypregn-4-ene- 3,1 1,20-trione.

Likewise, by using the 16a-methyl and 16,8-methyl compounds prepared in Example 3, there is obtained 9oc-tl'lfiuoromethyl-16a-methyl-l704,2l-dihydroxypregn 4 ene- 3,11,20-trione and 9a-trifiuoromethyl-16,8-methyl-17a,2ldihydroxypregn-4-ene-3,11,20-trione.

Example 5 A mixture of 0.5 g. of 9a-trifiuoromethyl-170:,21-dihydroxypregn-4-ene-3,l1,20-trione, 10 ml. of dioxane and 0.35 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is refluxed for 10 hours. The mixture is then cooled, filtered and evaporated to dryness. The residue is dissolved in acetone and this solution is then filtered through 10 g. of alumina and concentrated to yield 9u-trifiuoromethyl- 17o,2l-dihydroxypregna-1,4-diene-3,11,20-trione which is further purified by recrystallization from acetonezhexane.

By repeating the process of this example using as the starting material the 9a-trifiuoromethyl and 9u-difluoromethyl compounds of this invention obtained in Examples 2 and 4, there are obtained 9a-trifluoromethyl-16a-methyl- 17a,21-dihydroxypregna-1,4-diene-3,l1,20-trione, 90c trifluoromethyl-16B-methyl 1711,21 dihydroxypregna-1,4- diene-3,1l,20-trione, 9tx-difiuoromethyl-l7a,2l-dihydroxypregna-1,4-diene-3,l1,20-trione, 9a-difiuoromethyl 16ozmethyl-l711,2l-dihydroxypregna-l,4-diene-3,11,20 trione, and 9a-difiuoromethyl-16fl-methyl-l7ot,2l-dihydroxypregna-l,4-diene-3,11,20-trione.

Example 6 One gram of 9a-trifiuoromethyl-17a,21-dihydroxypregn- 4-ene-3,l1,20-trione and 2 g. of chloranil in 40 ml. of tbutanol are heated at reflux for 8 hours. The cooled re- Example 7 By repeating the process of Example using as the starting material the A compounds obtained in Example 6, the corresponding N fi-triene compounds are obtained, e.g. 9a-trifluoroethyl-l7u,2l-dihydroxypregna-1,4,6-triene- 3,11,20-trione, 9a-trifluoromethyl-16m-methyl 1704,21-dihydroxypregna-l,4,6triene 3,11,20 trione, 9zx-difl1l010- methyl-17a,2l-dihydroxypregna 1,4,6-triene-3,11,20-trione, 9a-difiuoromethyl-16B-methyl-17a,21-dihydroxypregna-1,4,6-triene-3,11,20-trione, etc.

Example 8 A mixture of 1 g. of 9u-trifluoromethyl-17a,2l-dihydroxypregna-4,6-diene-3,11,20-trione, 2 g. of chloranil and ml. of n-amyl alcohol are refiuxed under nitrogen for 24 hours. The mixture is then cooled, washed with a cold aqueous solution of 10% sodium hydroxide until the Washings are colorless, dried over sodium sulfate and evaporated. Chromatography of the residue on neutral alumina yields 9a-trifluoromethyl-17u,21-dihydroxypregna 1,4,6- triene-3,1l,20-trione which may be further purified thIough recrystallization from acetonezhexane.

Example 9 To a solution of 5 g. of 9a-trifluoromethy1-17a,2l-dihydroxypregn-4-ene-3,11,20-tri0ne in 200 ml. of chloroform are added 40 ml. of 37% aqueous formaldehyde and 5 ml. of concentrated hydrochloric acid. The mixture is stirred for 48 hours at room temperature and the two layers then separated. The aqueous layer is extracted with chloroform and the combined organic layer and chloroform extracts are washed with water to neutrality, dried over sodium sulfate and evaporated to dryness to yield 17a,20;20,2l bismethylenedioxy-9a-trifluoromethylpregn- 4-ene-3,11-dione which is recrystallized from methanol: ether.

By repeating the process of this example using the 17a,21-diol-20-keto derivatives prepared in Examples 2, 4, 5, 6 and 7 above as the starting material, there is obtained the corresponding 17a,20;20,2l-bismethylenedioxy derivaltive, e.g. 17a,20;20,21-bismethylenedioxy-9a-trifiuoromethylpregna-4,6-diene-3,1l-dione, 17a,20;20,21-bismethylenedioxy-9a-trifluoromethylpregna-1,4 diene 3,11-dione, 17a,20;20,21=bismethylenedioxy-9a-trifluoromethylpregna-1,4,6-triene-3,ll-dione, 17a,20;20,2l bismethylenedioxy-9a-trifluoromethyl-16a-methylpregn-4 ene-3,11- diorre, 17a,20;20,21-bismethylenedioxy-9a-difluoromethy1pregn-4-ene-3,1l-dione, etc.

Example 10 16 methylenedioxy-9a-trifluoromethylpregn 4-ene 36,11,8- diol which may be further purified byrecrystallization from acetonezhexane.

A mixture of 1 g. of the above 35,11B-diol in 20ml. of dioxane, and dicyanol,4-benzoquinone is allowed to stand at room terr1w perature for 3 hours. The solid formed during the reaction is removed by filtration and the filtrate evaporated to dryness. The residue is dissolved in acetone and filtered through 20 g. of alumina to yield 17a,20;20,21-bisrnethyr l-. enedioxy-9u-trifiuoromethyl-1lfi-hydroxypregn 4 err-3- one which may be further purified by recrystallization from acetonezhexane. t

A suspension of 1 g. of the thus-obtained A -3,-oxo compound in 10 ml. of 48% aqueous hydrofluoric acid is stirred at 0 C. for minutes. At the end of this time, the reaction mixture is neutralized with 5% aqueous potassium bicarbonate solution and extracted with ethyl acetate. These extracts are evaporated to dryness under reduced pressure and chromatographed on silica gel with 2:1 hexanezethyl acetate to yield 9a-trifluoromethyl-llfi, :,21 trihydroxypregn 4 ene 3,20 dione (9a-tri fiuoromethylhydrocortisone) which may be further purified through recrystallization from isopropanol.

Similarly, by using the other 9oc-trifluoromethy1 and 9a-difluoromethyl-3,1l-dione derivatives of this invention as the starting material in the process of this example, the corresponding 9a-trifiuoromethyland. 9a-difluoromethylhydrocortisones and prednisolones are obtained, e.g. 9atrifluoromethyl 11B,17o,21 trihydroxypregna-1,4-diene- 3,20-dione, 9a-trifiuoromethyl-l1B,17a,21-trihydroxy-16/3- methylpregna 1,4 diene 3,20 dione, 90c trifluoromethyl 11B,l7a,21 trihydroxy 16a methylpregna 1, 4-diene-3,20-dione, 9a-difiuoromethy1-11,8,17a,21-trihydroxypregn-4-ene-3,20-dione, etc.

Example 11 A mixture of 1 g. of 9a-trifluoromethyl-11B,17a,21- trihydroxypregn-4-en-3-one, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 9a-trifiuoromethyl- 11p,17,21-trihydroxypregn-4-ene-3,20-dione 21 acetate which may be further purified through recrystallization from acetonezhexane.

A solution of 1 g. of the above prepared ill-acetate in 50 ml. of tetrahydrofuran is added over a 30 minute period to a stirred suspension of 1 g. of lithium tri-t-butoxy aluminum hydride in 50 ml. of anhydrous tetrahydrofuran and this mixture is left standing at room temperature for 5 hours. To the mixture are cautiously added 5 ml. of ethyl acetate and 2 ml. of water. Sodium sulfate is next added, the mixture is filtered and the solid thus collected is washed with hot ethyl acetate. The combined organic solutions are then evaporated to yield 9u-trifluoromethylpregn 4 en 2O one 3fi,l1fi,l7a,21- tetrol-21-acetate which may be further purified through recrystallization from acetonezhexane.

Similarly, by using other carboxylic acid anhydrides in place of acetic anhydride in the process of this example, other 21-acylates are obtained, e.g. 21-propionate.

Likewise, through the use of other 9a-trifiuoromethyl and difluoromethyl corticoids of this invention prepared as described in Example 10, the corresponding 35,115, 17u,21-tetrahydroxy-2l-acylates are obtained, e.g. 9a-trifluoromethyl 16p methyl 3B,11B,17oc,21 tetrahydroxypregna 1,4 dien 20 one 21 acetate, 90: trifluorornethyl 3p,llfi,l7a,2l tetrahydroxypregna 4, 6 dien 20 one 21 acetate, etc. 1

Example 12 I A solution of 1 g. of 9a-trifluoromethyl-3fl,11 3,170, 21-tetrahydroxypregn-4-en-20-one-2l-acetate in 50 ml. of methanol is heated at reflux for 3 hours with a solution 1.1 molar equivalents of 2,3-dichloro-5,6

of .2 g. of potassium hydroxide in 1 ml. of water. The reaction mixture is then poured into ice, water and the solid whichforms. collected by filtration, washed with water toneutralityanddried to yield 9a-trifiuoromethyl- 3}9,11,8,l7a,21 tetrahydroxypregn 4 en 20 one which is recrystallized from methylene chloridezether.

Similar y, by-use of, the process of this example, the other 21-acylates of this invention'are hydrolyzed to the corresponding freeZI-hydroxy derivative.

Example 13 A mixture ofi lil g. of 9a-. trifluoromethyl-3 3,11fi,17u,21- tetrahydroxypregn-4-en-20-one-2l-acetate, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 1 hours. The mixture is then poured into icewat er and .the solidwhich forms is collected by filtration, washed with Waterand dried to yield 911 trifluoromethyl 3B,11fl,17oc,21 tetrahydroxypregn- 4-en-20-one-3,2l-diacetate which ;may be further purified through recrystallization from acetone:hexane.

' In a similar manner, the 3,2l-diacylate, of other 9a-trifiuoromethyl and 9adifluoromethyl compounds of the present invention are obtained.

. Example 14 Example 15 A solution of l g. of 9a-trifiuoromethyl-3fl,17a,21-trihydroxypregn 4 en 11,20 dione 3,21 diacetate in 50 ml. of methanol is left standing for 3 hours at 0 C. with a solution of 0.25 g. of potassium hydroxide in 1 ml. of water. The reaction mixture is then poured into ice water and the solid which forms collected by filtration, washed with water to neutrality and dried to yield 9a-trifiuoromethyl 3fi,l7a,21 trihydroxypregn 4 en 11, ZO-dione which is recrystallized from methylene chloride: ether.

Example 16 Two milliliters of dihydropyran are added to a solution of 1 g. of 9a-trifluoromethyl-3BJ1fi,17a-21-tetrahydroxypregn-4-en-20-one-2l-acetate in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooled solution. This mixture is allowed to stand at room temperature for four days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 3 9-(tetrahydropyran- 2'-y1oxy) 9a trifluoromethyl 11B,170c,21 trihydroxypregn-4-en-20-one-2l-acetate which is recrystallized from pentane.

Similarly, by using the other 9a-trifiuoromethyland 9a-difiuoromethyl compounds of the present invention having a free 3/3-hydroxy group, the corresponding 3fl-tetrahydropyran-Z-yl ethers are obtained.

Likewise, by the use of dihydrofuran in the process of this example in lieu of dihydropyran, the corresponding 3,H-tetrahydrofuran-2-yl ether is obtained, e.g. 3,8-(tetrahydrofuran-2'-yloxy)-9a-trifluoromethyl-11fi,17a,21 trihydroxypregn-4-en-20-one-2l-acetate.

Example 17 By repeating the process of Example 12 using the 3,6- tetrahydropyran-Z-yl ethers and 3/3-tetrahydrofuran-2-yl ethers of Example 16 as the starting material, there is obtained the corresponding free 21-hydroxy compound, e.g. 3fl-(tetrahydropyran-Z'-yloxy)-90: trifluoromethyl- 1 113,1701,21-trihydroxypregnr4-en-20-one.

Example 18 By subjecting 3,6-(tetrahydropyran-2'-yloxy) 9a trifluoromethyl-l1B,17a,21 -trihydroxypregn 4 en-20-one- 2l-acetate to the procedure of Example 14, there is obtained BB-(tetrahydropyran-Z'-yloxy)-9d trifluoromethyl- 17a,2l-dihydroxypregnA-ene-l1,20-dione-21-acetate.

Upon treatment of this compound with potassium hydroxide in aqueous methanol as described in Example 12, there is obtained the corresponding free ZI-hydroxy compound.

The other 3-ethers of the present invention may be subjected to the procedure of this example to obtain similar compounds, e.g. 3-fi-(te'trahydrofurain 2 yloxy)-9a-trifluorom ethyl-17a,21' dihydroxy-pregn 4 ene 11,20- d'ione-Zl-acetate and the corresponding freeZI-hydroxy compound. i v

Example 19 One gram of 9a-trifiuoromethyl 3j3,llfi,l7a,21 tetrahydroxypregn-4-en-20-one 3,21 diacetate is allowed to stand at room temperature for 15 hours with 0.25 g. of potassium bicarbonate in 10 ml. of water and ml. of methanol. At the end of this time, the methanol is evaporated under reduced pressure and the residue is extracted with ethyl acetate and water. Evaporation of the ethyl acetate from these extracts yields 9a-trifiuoromethyl- 3,6,11,8,17a,21-tetrahydroxypregn-4-en-20-one 3 acetate which is collected by filtration and recrystallized from acetonezhexane.

By subjecting the other 35,21-diacylates of the present invention to the process of this example, the corresponding free 21-hydroxy compounds are obtained, e.g. 9a-trifiuoromethyl-3/i, ;,21 trihydroxypregn 4 ene- 11,20-dione-3-acetate, 9a-trifiuoromethyl 16oz methyl- 3 8,l7a,21-trihydroxypregn 4 ene 11,20 dione 3- acetate, 9u-difiuoromethyl-3fi,17a,2l trihydroxypregna- 4,6-diene-11,20-dione 3 acetate, 90: trifluoromethyl- 3p,11 3,17a,21-tetrahydroxypregna 1,4 dien 20 one- 3-acetate, etc.

Example 20 Example 21 5 milliliters of dihydropyran are added to a solution of 1 g. of 9u-trifiuoromethyl-3fl,17-a,21-trihyd-roxypregn-4- ene-11,20-dione in 20 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.5 g. of p-toluenesulfonyl chloride is added to the cooled solution. This mixture is allowed to stand at room temperature for four days and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 35,21 bis(tetrahydropyran-2' yloxy) 9a trifluoromethyl 11,20-dione which is recrystallized from pentane.

Other bis ethers may "be cedure from other 3B,21-diol compounds of the present invention, e.g. 35,21-bis(tetrahydropyran-2-yloxy)-9a-trifluoromethyl-l1B,17a-dihydroxypregn 4 en 20 one. etc. Similarly, by using dihydrofuran in place of dihydro- 17o: hydroxypregn 4 eneprepared by the above pro-.

pyran -in the above procedure, the bis-tetrahydrofuranyl ethersi-are-obtained. Tl r example 22 1-; I

A mixture of 2.0' gf of' 9'ot-trifluoromethyl-17a,2l-dihydroxypregn-4-ene-3,11,20-trionef4 ml. of methylorthovalerate, 4.0 ml.- of dry. dirnethy lf ormam ide, and .20 mg. of p-toluenesulfonic ,acidis stirred and refluxed for20 minutes frhe mixtureis then cooled, to about roorn ternperat ire, about three ,drops-of pyridine areadded and then the mixture concentrated to dryness under; reduced pressure. .The residue then treated .with methanol from which the;1 7,2lfi;)rthoester crystalizes. A.mixtu re of about 1 ,5 got the above'. 1 7,2 l-orthoester, 120 m1. of methanol,- 10 ml. of water and}. m1.,,of l- IS-hydr hloIicacid isstirred and refluxed for 20 minut kIhf i i a m x r h filts sd -end a o a to. dryness...T he residue is purified frommethanol to.yield 9 m trifluoromethyl; 17 ,21 -,dihydroxypregn ,4 ,ene- -t xat..

By use of the process of this example, other l7e.- acyl ate derivatives of the 9a.-trifiuoro rnethyl and 9a-diiluoromethyl compounds of the present invention are obtained. Thus using 9m-trifiuorornethyl-prednisolone, 9a-trifluoromethyl-prednisone, 9m-trifluorome'th'yl-loflfrnethyl-prednisolone, 9a-ditfuoromethyl-cortisone, fre'spect'ively, as' the startiiig material, the corresponding l7a-valerate is obtained. v

Likewise, by the use of methylorthoacetate, and "the like in place of methylorthovalerate in the process of this example, the corresponding l7uacylate, e.g. Net-acetate is obtained, for example, 9a-trifiuoromethyl-cortisone-17- acetate, 9ot-trifiuorornethyl-prednisolone 17 acetate, 90:- trifluoromethyl hydrocortisone 17 -acetate, 90: difluoromethy'l-cortisone-l7-acetate, 90c trifluo'ro-l6e methylprednisolone-l7-ac'etate, etc.- I Example 23 V v A solution of 5 g. of 9a-trifiuorornethyl-17a,20;20,2lbismethylenedioxypregn-4-ene 3,11 dione in 50 ml. of aceticanhydride and 50 ml. of acetyl chloride is heated at reflux for 4 hours under nitrogen. The reaction mixture is then distilled to almost dryness, cooled, and diluted with ether. The organic phase is washed with water, aqueous 5% sodium bicarbonate solution and again with Water, dried over sodium sulfate and evaporated to yield 9a-t1'ifluoromethyl-l7a,20;20,2l bisrnethylenedioxy-Zl-acetoxypregna-3,5-dien-1l-one which may be recrystallized from acetonezhexane.

A solution of 6 g. of the above enol acetate in 100 ml. of 95% ethanol and 35 ml. of tetrahydrofuran iscooled to 10 C. and added dropwise over a 1 hour period to a stirred, .cooled solution of 6 g. of sodium borohydride in 50 ml. of 80%..ethanol, the reaction temperature being maintained below 5 C. Upon completion of addition, the solution is allowed to stand at 0 C. to 5 C. for- 2 hours. Two hundred milliliters .of 10% sodium hydroxide solution are then added and the solution heated at the boiling point for minutes. The solvent is evaporated under reduced pressure and the residue is acidified with hydrochloric acid. The solid which forms is collected by filtration, washed with water and dried to yield 9a-trifiuoromethyl-l7a,20; 20,2l-bismethylenedioxypregn- 5-ene-3fi,llB-diol which may be further purified by recrystallization from acetone. -A solution of 2.5 g. of the above A compound in 100 ml;of chloroform is cooled to 0 C.'and mixed with a solution of 1.1 molar equivalents of monoperphthalic acid in ether. The mixture is allowedto stand at room temperature for 20 hours and then diluted with water. The organic layer is separated, washed with aqueous sodium bicarbonate solution and then with water to neutrality, dried over sodium sulfate and evaporated to dryness to yield 9a-trifluor'omethyl-170 20;-20,2l-bismethylenedioxy- 5a,6a-oxido-pr'egnane-3,3,llB-diol which may be further purified by recrystallization from ac'etone:hexane.

20 To a stirred solution of 20 ml. of 4 N methylmagnesium bromide in ether-is added a solution of 1 g. of the above 5a,'6a -oxido compound in 30 ml. of dry'tetrahydrofur'an'andthe stirred mixture is heated at reflux temperatures for'3 0 minutes. The refiux' condenser is then replaced by 'a' calcium chloride drying tube and the ether is'all'owed to escape. When the internal temperature is 54 C., the condenser is returned and the mixture refluxed for an additional 4-hour period. Two hundred milliliters of a saturated ammonium chloride solution are then slowly added to the cooled mixture which is then stirred for' '15 minutesand extracted with ethylacetate. These extracts arewashed with water, dried over sodium sulfate and: evaporated to dryness to yield 6fl-rnethyl-9a-trifluoromethyl 17 a, 20', 20, 2l bisrnethylenedioxypregnane-3550i, llB-triol which is recrystallized from aqueous methanol.

To a stirred solution of l g. of the thus-obtained compound'in 10 ml. of acetone, cooled to 0 C., is added under nitrogen a solution of 8 N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 ml. of concentrzited' sulfuric acid'arid diluting with water to 100 ml.) until the color of the reagent persists in the mixture. The mixture is then stirred for 5 minutes at 0-5" C. and diluted with water. The solid which forms is collected by filtration, washed with water anddried under vacuum to yield 66 methyl 9a trifluorornethyl 17a,20; 20,2l-bismethylenedioxy 5a hydroxy-pregnane-3,l l-dione which may be further purified by recrystallization from acetone: hexane." I

A solution of l g. of the above 6fl-methyl-3,ll-dione in 20 ml. of methanol containing 0.2 g. of sodium hydroxide is allowed to stand for 1 /2 hours at room temperature. The mixture is then poured into water and ext'racted with methylene chloride. Theseextracts are then evaporated to yield 6u-methyl-9a-trifiuoromethyl-l7a,20; 20,21 bismethylenedioxypregn 4 ene-3,ll-dione which may be recrystallized from acetonezhexane.

By subjecting 6a methyl 9a trifluoromethyl-l7a,20; 20,2l-bismethylenedioxypregn-4-ene-3,1l-dione to reduction with sodium borohydride followed by selective oxidation .at C43 and then removing the bismethylenedioxy protecting group in accordance with the procedure of Example 10, there is obtained- 6a-methyl-9a-trifiuoromethyl-1 1,3,17a,2l-trihydroxypregn-4-ene-3 ,20-dione.

By repeating the process of this example using as the starting material the 17,20; 20,2l-bismethylenedioxy derivative of 9a-trifluoromethyl-16e-methylpregn-4-ene- 3,11 dione, c trifiuoromethyl-l6fi-methylpregn-4-ene- 3,11 dione, 9o; difluoromethylpregn 4 ene-3,l l-dione, there is obtained 6a,l6a-dimethyl-9u-trifiuoromethylhydro cortisone, 60:,165 dimethyl 9a-trifluoromethylhydro cortisone, 6a-methyl-9u-difluorornethylhydrocortisone, respectively. I

By subjecting the above compounds to the process of Example 5, there are obtained the corresponding A compounds, that is, 6a-methyl-9a-trifluoromethylprednisolone, 611,16 dimethyl-9a-trifluoromethylprednisolone, 6ct,l6[3, dirnethyl- 9u trifiuoromethylprednisolone and 6a-methyl- 9t-difluoromethylprednisolone.

By'repeating the procedure of Example 6, using the above 9a-trifluoromethyl and 9a-difluoromethyl compounds, the corresponding C-6, 7 dihydro derivatives are obtained, for example, 6 methyl 9a trifluoromethyl- 11;8,l 7a,21-trihydroxypregn-4,6-diene-3,20-dione 6,16a-dimethyl 9a-trifiuoromethyl-11,8,l7a,2l-trihydroxypregnal,4,6-triene-3,20-dione, etc.

Example 24 A mixture of 1 g. of 6a-methyl-9a-trifluoromethyh 1lp,17a,21 trihydroxypregn 4 ene-3,20-dione, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 641 methyl 9a trifiuoromethyl-llB,17a,21-trihydroxypregn-4-ene-3,20-dione-2l-acetate which may be further purified through recrystallization from acetonethexane.

Example 25 Example 26 A mixture of 1 g. of 6'a-methyl-9ot-trifl'uoromethyll7a,21-dihydroxypregn-4-ene-3,11,20-trione-2l-acetate, 1 g. of p-toluenesulfonic acid monohydrate, 50 ml. of acetic acid and 2 ml. of acetic anhydride is allowed to stand at room temperature for 24 hours, and then is poured into water and stirred. This mixture is then extracted with methylene chloride and these extracts are 'dried and evaporated. The residue is then dissolved in 250 in]. of methanol containing 5 ml. of concentrated hydrochloric acid. After refluxing for one hour, the mixture is neutralized with an aqueous solution of potassium bicarbonate and evaporated. The residue is extracted with methylene chloride, and the methylene chloride extract is washed with water to neutrality, dried and evaporated to yield 6a-methyl-9a-trifiuoromethyl-17u,21-dihydr0xypregn 4 ene 3,11,20-tri0ne-17,2l-diacetate, which is re crystallized from acetonezether.

Example 27 By treating 6a-methyl-9u-trifiuoromethyl-171,2l-dihydroxypregn-4-ene-3,11,20-trione with chloranil in t-butanol by the procedure described in Example 6, there is obtained 6-methyl-9a-trifluoromethyl l7ot,2l-dihydroxypregn-4,6-diene-3,l1,20-trione.

' Treatment of this 4,6-diene compound with selenium dioxide according to the procedure of Example 5 to effect dehydrogenation at C1,2, furnishes 6-n1ethyl 9a-trifluoromethyl l7a,21-dihydroxypregna 1,4,6-triene 3, 11,20-trione.

Example 28 By repeating the process of Example 5 using 6a-methyl- 9a-trifluoromethyl l7a,2l-dihydroxypregn 4-ene-3,11,- 20etrione as the starting material, there is obtained 6amethyl 9a-trifiuoromethylprednisone (6a-methyl-9a-trifluoromethyl l7a,2l-dihydroxypregna 1,4-diene-3,1l, 20-trione).

Example 29 To a suspension of 1 g. of 9a-trifluoromethyl-170:,21- dihydroxypregn-4-ene-3,11,20-trione in 7.5 ml. of anhydrous, peroxide-free dioxane are added 1.2 ml. of freshly distilled ethyl orthoformate and 0.8 g. of p-toluenesulfonic acid. The mixture is stirred at room temperature for minutes and then allowed to stand at room temperature for 30 minutes. There is then added 0.8 ml. of

pyridine, followed by water until solidification occurs.

This solid is collected by filtration, washed with water and air dried to yield 3-ethoxy-9a-trifluoromethyl-17a, 21-dihydroxypregna 3,5-diene-1l,20-dione which is recrystallized from acetone:hexane.

A stream of perchloryl fluoride is passed through a solution of 1 g. of the above enol ether in 25 ml. of dimethylformamide, cooled to 0 C., for 5 minutes. After being allowed to slowly attain atemperature of 20'C., the solution is poured into water and extracted with ethyl acetate. These extracts are washed with saturated aqueous sodium bicarbonate solution and with 'water to neutrality, dried over sodium sulfate and evaporated to dryness. The residue is then chromatographed on alumina to separate the 6a-flUOIO and 6fl-fiuoro isomers. The latter, which predominates, is dissolved in 50 ml. of glacial acetic acid and through this solution is passed a stream of dry hydrogen chloride for a period of 24 hours and at a temperature of 15 C. The mixture is poured into cold water and the solid which forms is collected by filtration, washed with water and dried to yield 6a-fluoro-9u-trifiuoromethyl-17a,2l-dihydroxypregna 4-ene-3,ll,20-trione (6a-fluoro-9a-trifiuoromethylcortisone) which is recrystallized from acetonezhexane.

By repeating the process of the process of this example using as the starting material 9a-trifluoromethylhydrocortisone, 9a-difiuoromethylcortisone, 9a-trifiuoromethyl- 16B-methylhydrocortisone, 9owtrifiuoromethyl-16a-meth ylhydrocortisone, 9a-trifluoromethyl 16a-methylcortisone, 9ot-trifluoromethyl l6B-methylcortisone and 9adifiuoromethyl 16,8-methylcortisone, there are obtained the corresponding 6a-fiuoro compounds.

By using the above 6a-fluoro-9a-trifluoromethyl and 6a-fiuoro-S a-difluoromethyl compounds as the starting materials in the process of Example 5,. the corresponding A derivatives are obtained e.g. 6a-fluoro-9a-tri-fluoromethylprednisone, 6a-fluoro-9a-trifiuoromethylprednisolone, 6u-fiuoro-9a-trifluoromethyl 16B-methylprednis olone, 6u-fluoro-9a-trifiuoromethyl 16a-methylprednisolone, 6a-fiuoro-9a-difiuoromethylprednisone.

Example 30 By treating 6a-fluoro-9u-trifluoromethylcortisone according to the acylation procedure of Example 22, the corresponding 17a-acylate is obtained.

Similarly, the other 6-fluoro-9a-trifluoromethyl and 6- fiuoro-9a-difluoromethyl compounds of the present invention are transformed into the corresponding l7a-acylate, e.g. 6a-fiuoro-9a-trifluoromethyl 16,6-methylprednisolone l7-valerate, 6a-fluoro 16a-methylprednisolonel7-valerate, 6a-fluoro 9a-difluoromethylprednisone-17- acetate, etc.

Example 31 A mixture of 22 ml. of trimethylacetyl chloride, and 8.82 g. of 6u-fluoro-9a-trifiuoromethyl 16a-methylprednisolone, dissolved in ml. of pyridine is slowly added to 350 ml. of pyridine under continuous stirring in a nitrogen atmosphere at 0 C. The reaction mixture is then left to stand under nitrogen at room temperature and is thereafter poured into ice-cooled diluted hydrochloric acid and the resulting precipitate extracted with acetic acid ether. The extract is then washed with hydrochloric acid and sodium carbonate and concentrated under vacuum to furnish the ZI-trimethyl acetate.

Example 32 By treating 6a-fiuoro-9a-trifluoromethyl 17a,21-dihydroxy-pregn-4-ene-3,l1,20-trione according to the dehydrogenation procedure of Example 6, there is obtained 6-fiuoro 9a-trifluoromethyl 17a,2l-dihydroxypregna- 4, 6-diene-3,l 1,20-trione.

Example 33 To a solution of 5 g. of 9a-trifluoromethyl-l7a,21-dihydroxypregna 4,6-diene-3,11,20-trione in 200 ml. of chloroform are added 40 ml. of 37% aqueous formaldehyde and 5 m1. of concentrated hydrochloric acid. The 48 hours at room temperature and the two layers then separated. The aqueous layer is extracted with chloroform and the combined organic layer and chloroform extracts are washed with water to neutraL 23 ity, dried over sodium sulfate and evaporated to dryness to'yield 9a-trifluoromethyl 17oc,20; 20,2l bismethylenedioxypregna-4,6-diene-3,l1-dione which is recrystallized from methanolzether. T 'By repeating the process of this example using as the starting material, other 9u-trifluoromethyland 9a-difluoromethyl-6,7-dehydro derivatives of cortisone and bydrocortisone, the corresponding 17a,20; 20,21-bismethylenedioxy compounds are obtained e.g. 17a,20; 20,21-bismethylenedioxy 9ot-trifluoromethyl 16a-methyl 11B- hydroxypregna 4,6-dien-3-one,-- 17oc,20; 20,2l-bismethylenedioxy-9a-difluoromethyl 16ci-IIl6thYl llfi-hydroxyp'regna-4,6-die'n-3-one, etc. Y

" Example 35 i To a gently refluxing and stirred solution of 1 g. of the compound of the preceding example in 8 ml. of dimethyl diethyleneglycol ether is added in a dropwise fashion over a two-hour period, a solution of 30 equivalents of sodium chlorodifluoroacetate in 30 ml. of dimethyl diethyleneglycol ether. At the end of the reaction period which may be followed by the U.V. spectra, the mixture is filtered and evaporated in vacuo to dryness; The residue is added to 10% methanolic potassium hydroxide and this mixture is heated briefly at reflux and poured into ice water. The solid which forms is collected, Washed with water, dried and chromatographed on alumina, eluting with methylene chloride, to yield 6a,7a-difluoromethy1ene-9a-trifluoromethyl-l7a,20; 20,21-bismethylenedioxypregn-4-ene-3,11- dione.

A suspension of 1 g. of this compound in 10 ml. of 48% aqueous hydrofluoric acid is stirred at C. for 90 minutes. At the end of this time, the reaction mixture is neutralized with 5% aqueous potassium bicarbonate solution and extracted with ethyl acetate. These extracts are evaporated to dryness under reduced pressure and chromatographed on silica gel with 2:1 hexanezethyl acetate to yield 6u,7a-difluoromethylene-9u-trifluoromethylcortisone which may be further purified through recrystallization from isopropanol. In a similar manner, the other 9a-trii?luoromethy1-A and 9oz-difluoromethyl-A compounds of the present invention are converted into the 6a,7a-difluoromethylene derivative, e.g. 6a.,7a-difluoromethylene-9a-trifluoromethyl 16a-methyl-hydrocortisone, 6a,7u-difluoromethylene- 9a-difluoromethyl-16u-methyl-hydrocortisone.

Example 36 A solution of 1 g. of 9a-trifluoromethyl-17,20; 20,21- bismethylenedioxypregna-4,6-diene-3,ll-dione in ml. of dimethylsulfoxide is added to a solution of 1 equivalent of dimethylsulfoxonium methylide in dimethylsulfoxide. The mixture is stirred under nitrogen at room temperature for 20 hours'and at 50 C. for about 7 hours. Fifty ml. of water are then added and the resulting mixture is extracted four times with 100 ml. portions of ethyl acetate. The combined extracts are washed with water and saturated aqueous sodium chloride solution, dried, and evaporated to dryness. This residue is then chromatographed on silica, eluting with etherzmethylene chloride (1:9) to yield 6m,7u-methylene-9oc-trifluoromethyl-170,20; 20,21- bismethylenedioxypregn-4-ene-3,1 l-dione.

A suspension of 1 g. of this compound in 10 ml. of 48% aqueous hydrofluoric acid is stirred at 0 C. for 90 minutes. At the end of this time, the reaction mixture is neutralized with 5% aqueous potassium bicarbonate solution and extracted with ethyl acetate. These extracts are evaporated to dryness under reduced pressure and chromato graphed on silica gel with 2:1 hexanezethyl acetate to yield 6a,7u-methylene-9u-trifluoromethylcortisone which may be further purified through recrystallization from isopropanol.

Likewise, by repeating the process of this example using other 9u-trifluoromethyl-A and 9a-difluoromethyl-A compounds of the present invention, there are obtained 'drofluoric acid according to 24 other 606,70L-1Il6ll1Yl6I16 derivatives, e.g. 6u,7u'-methy lenctrifluoromethyl hydrocortisone, oafla-me'thylen'e-9ddifluoromcthyl cortisone, 6a,7a 1 methylene-9a trifluoromethyL16m-methy1-cortisone, and 6a,7u-methylene-9atrifluoromethyl-l6a-methyl-hydrocortisone.

Example 37 A mixture of 0.5 g. of 6u,7a-difluoromethylene-9u-tr-ifluoromethyl l7a,21 dihydroxypregn 4 ene 3,11- 20-trione, 10 m1. ofdioxane and 0.35 g. of 2,3-dichloro-5, 6-dicyano-1,4-benzoquinone is refluxed for 10 hours. The mixture is then cooled, filtered and evaporated to dryness. The residue is dissolved in acetone and concentrated to yield 600,70: difluoromethylene 9a trifluoromethylprednisone which is further purified by. recrystallization from acetonezhexane. 7 By the use of the process of this example, other 6u,7e difluoromethylene and 6u,7u-methy1enederivatives ofthe 90: trifluoromethyl A and 90: difluoromethyl A com pounds of this invention are converted into the corresponding A -diene derivativcs, e.g. oafla-difluoromethylene-9 a-trifluoromethyl-l6a-methyl-prednisolone. and' 6a, 7a. methylene 9a trifluoromethyl 16a methyl pred-, nisolone. 1: 1

Example 38 To a stirred solution of 3 g. of 9a-trifluoromethyl-17a, 20', 20,21-bismethylenedioxypregn-4-ene-3,1l dione in 60 ml. of anhydrous benzene is added, with cooling and under nitrogen, a suspension of 3 ml. of ethyl formate and l.3 g. of sodium hydride in mineral oil. The mixture is stirred at room temperature for 24 hours and hexane is then added until complete precipitation occurs. The solid which forms is collected, dried under vacuum and suspended in aqueous hydrochloric acid. This suspension is stirred at room temperature for half an hour and then filtered. The solid thus collected is washed with water and dried to yield 2 hydroxymethylene 9a trifluoromethyl -17a,20', 20, 2l-bisrnethylenedioxypregn 4 ene 3,11 dione which is recrystallized from methylene chloridezhexane. l

To a suspension of 1.2 g. of the above 2-hydroxy meth-v ylene-9u-trifluoromethyl compound and 0.22 g. of sodium acetate in 25 ml. of ethanol is added under nitrogen 0.25 g. of p-fluorophenylhydrazine hydrochloride. The mixture is heated at reflux under nitrogen for one hour and then evaporated to dryness. The residue is washed three times with 2.5 N hydrochloric acid, three timeswith 2.5 N sodium hydroxide and finally with water, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to yield a residue containing 9u-trifluoromethy1- 17a,20;20,21 bismethylenedioxypregn-4-en-11-oue-3,2-C- 2-p-fluorophenylpyrazole which may be recrystallized from methanol.

The thus-obtained pyrazole is treated with aqueous hythe procedure described in the second paragraph of Example 36 above to yield 9u-trifluo romethyl 1711,21 dihydroxypregn 4 ene 11,20- dione-3,2-C-2'-p-fluorophenyl pyrazole. 1

By repeating the process of this example using asthe starting material other 9a-trifluoromethyl-A and 9oc-Cllfluoromethyl-A compounds of this invention, the correlsponding pyrazole derivatives are obtained, e.g.

Similarly, by using other hydrazines, e.g. phenyl hydrazine hydrochloride, in place of p-fluorophenylhydrazine hydrochloride in the process of this example, the corresponding 3,2-C-2'-phenylpyrazoles are obtained, e.g. 9o: trifluoromethyl-17u,21-dihydroxypregn-4-ene-l1,20- dione-3,2-C-2'-phenylpyrazole, etc.

Similarly, use of an equivalent amount of hydrazine hydrate in the foregoing procedure, the corresponding 2'- unsubstituted-pyrazoles are obtained, e.g. 9a-trifluoromethyl 17a,21-dihydroxypregn-4-ene-ll,20-dione-3,2-C pyrazole.

Likewise, by the use of other hydrazines such as m and p-methylphenylhydrazine, o-, mand p-methoxyphenylhydrazine and o-, mand p-chlorophenylhydrazine in the foregoing procedure, there are obtained the corresponding 3,2-C pyrazoles substituted in the 2'-position by o-methylphenyl, m-methylphenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, ochlorophenyl, m-chlorophenyl, and p-chloropenyl, respectively, preferably para compounds.

Example 39 A culture of Streptomyces roseochromogenus A.T.T.C. No. 3347 is prepared in an inclined agar medium containing 1% of glucose and 1% of yeast extract. 1 cc. of a suspension of this culture is then used to inoculate each one of a series of 250 cc. flasks containing 50 cc. of a sterilized aqueous medium of 2% peptone and 5% corn syrup; the mixture is then incubated in a shaking machine at 28 C. under aeration for a period of 2448 hours. There is thus obtained a vegetating growing culture of Streptomyces roseochromogenus which is used for the subsequent incubating of the steroid.

g. of 9a-difluoromethyl-l7u,21-dihydroxypregn-4- ene-3,11-dione (9a-difluoromethyl-cortisone) is added to each 50 cc. of the vegetating culture of Streptomyces roseochromogenus, obtained as described above. The mixture is stirred for 48-72 hours with aeration and then extracted several times with methylene dichloride. The extract is Washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure.

The residue is purified by chromatography on silica thus giving 9u-difiuoromethyl-1oa-hydroxy-cortisone.

Example 40 Example 41 To 120 ml. of acetone containing 1 g. of 9wdifluoromethyl 16a,17u,21-trihydroxypregn-4-ene-3,1l-dione are added 30 drops of 70% perchloric acid. The mixture is allowed to stand 1 hour at room temperature, 30 drops of pyridine are added and th solution is evaporated to dryness under reduced pressure. Thirty milliliters of water are added to the residue and this mixture is extracted several times with ethyl acetate. The combined extracts are washed to neutrality with water, dried over sodium sulfate and evaporated to dryness. The residue upon trituration with methanol yields 16a,17u-isopropylidenedioxy 9a-difluoromethyl-2l-hydroxypregn-4-ene-3, ll-dione which is recrystallized from methanol.

By applying the foregoing procedure to other 9a-trifluoromethyl-16u,17a-diol and 9a-difluoromethyl-16a,l7adiol compounds of the present invention, the corresponding 16a,17u-acetonide derivatives are obtained, e.g. the

1602,17a-21C6t011id6 of 9a-trifiuoromethyl-la-hydroxyprednisolone, 9a-trifluoromethyl-6u-fluoro-16u-hydroxy-cortisone, 9a-difiuoromethyl-6a-fluoro-16m-hydroxyprednisone, 9a-trifluoromethyl-6a-fluoro-l 6a-hydroxyprednisolone, 9a-trifluoromethyl-6-fiuoro-6,7-dehydro-1oat-hydroxyprednisolone, 9a-trifluoromethyl-Got-methyl-16a-hydroxycortis0ne, 9a-trifluoromethyl-6a,7o-difluoromethylene-1Got-hydroxyprednisone, 9a,trifiuoromethyl-6a,7a-difluoromethylenel 6a-hydroxyhydrocortisone, 9a-trifiuoromethyl-6-methyl-6,7-dehydro-16a-hydroxycortisone, 9a-trifluoromethyl-6fi-fiuoro-6a,7ot-difiuoromethylene 16a-hydr0xyco1tisone, etc.

The 21-acylate of the foregoing compounds can be obtained by treatment with a carboxylic anhydride, e.g. acetic anhydride, propionic anhydride, and the like, in pyridine according to the method of Example 26 furnishthe corresponding 2l-acetate, 21-propionate, and the 1 e.

Example 42 Example 43 A mixturecontaining 1 g. of 9a-trifiuoromethyl-l7aacetoxy-21-hydroxypregn-4-ene-3,11,20-trione, 10 ml. of

phase is then washed with water, dried and evaporated to dryness to yield 9o -trifluoromethyl-2l-hydroxypregn-4- ene-3,I1,20-trione.

Using the process of this example, other 9a-trifiuoromethyl and 9a-difluoromethyl derivatives of this invention having a free hydroxy group or an ester group, preferably the acetate, at C-17 can be converted into the 17-desoxy derivatives.

Example 44 To 50 ml. of a 0.43 N solution of chromous chloride in acetic acid is added a solution of l g. of 9u-difiuoromethyl 17a acetoxy-2l-hydroxypregn-4-ene-3,l1,20- trione in aqueous acetic acid, under nitrogen. After about 30 minutes at room temperature, the reaction mixture is diluted with methylene chloride and ice water. The reaction mixture is then separated and the organic phase is washed, dried and evaporated to yield 9a-difiu0r0- methyl-21-hydroxypregn-4-ene-3,11,20-trione which may be purified by crystallization from acetonezpetroleum ether.

27- What-is claimed is: I i

1; A compound selected from the group consisting of those having the formulas wherein X is selected from the group consisting of difiuoromethyl and trifiuoromethyl; Y is selected from the group consisting of hydrogen and fluoro; Z is selected from the group consisting of a saturated bond and an ethylenically unsaturated bond between carbon-1 and carbon-2; R is selected from the group consisting of @O and V wherein R" is selected from the group consisting of hydroxy, a carboxylic acyloxy group of less than 12 carbon atoms, tetrahydropyran-2-yloxy, and tetrahydrofuran-Z- yloxy; R is selected from the group consisting of C=O and R is selected from the group consisting of hydroxy anda carboxylic acyloxy group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, fiuoro and methyl; R is selected from the group consisting of hydrogen, hydroxy, and a carboxylic acyloxy group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, alpha hydroxy, alpha methyl, and beta methyl; R and R together form the group at the 16a,l7a-position wherein each of R and R is selected from the group consisting of hydrogen and a hydrocarbon group of up to 8 carbon atoms; and R is selected from the group consisting of hydrogen, phenyl, chlorophenyl, fiuorophenyl, methoxyphenyl and methylphenyl, provided that when R is alpha hydroxy that R is selected from the group consisting ofhydroxy and a carboxylic acyloxy group of less than 12 carbon atoms.

2. A compound according to Formula Aof claim 1 28 wherein Z is an ethylenically unsaturated bond'betwe'en carbon-1 and carbon-2, R is C=O; and R is o 3. compound according to claim Z WhereinR? and R4 are each hydroxy and R and Riare each hydrogen. 4. A compound accordirigto claim z wherein R tand R? are each hydroxy, R is fluoro and R? is hydrogen.

51A compoundaccording to claim 2, wherein R? and R, ar e each hyfdroxy, R is fluoro, andR is alpha methyl. difAcompound according to claim Z wherein R is hyentanoyloxy and R alpha methyl. V g I A compound according to claim'z wherein R? and R are each hy'dro'xy, R is methyl; and R is hydrogen.

[81 A compound according to claim 2 wherein R and R are each hydroxy, R is hydrogen, and R is beta methyl. I t

9. A compound accordingto claim 2 wherein R is hydroxy, R is hydrog'en, R* is pentanoyloxy and R "is beta methyl.

10. A compound according to claim 2 wherein R 'and R are each hydroxy, R is fluoro, and R is beta methyl.

11. A compound according to claim 2 wherein R is hydroxy, R isifluoro, R is pentanoyloxy, and R is beta 12. A com-pound according to claim 2 wherein R is hydroxy, R is fluoroyand R and R together form=the group P i ....0 RG' at the l6a,17a-positiofn wherein each of R and R' is selected from the group consisting'of hydrogen and a hydrocarbon group ofup to '8carbon atoms.

13. A compound according to claim 2 wherein R is hydroxy, R is hydrogen, and R and R together form the group jo\ /R .....o R at the l6oz, 17oc-pOsitiOn wherein each of R and R is selected from the group consisting of hydrogen and a hydrocarbon group of up to 8 carbon atoms.

14. A compound according to claim 2 wherein R is trimethylacetoxy, R is fluoro, R is hydroxy and R is alpha methyl. 7

15. A compound according to Formula A ofclaim 1 wherein Z is an ethylenically unsaturated bond between carbon-1 and carbon-2 and R is C=O.

16. A compound according to Formula A of claim 1 wherein R and R are each hydroxy and R is C O.

17. A compound according to Formula B of claim 1 wherein R is C .-O, R is R and R are each hydroxy, R is methyl, R is alpha methyl, and Z is an ethylenically unsaturated bond between carbon-l and carbon-2.

18. A compound according to Formula C of claim 1 wherein R is C=O, R is R and R are each hydroxy, R is hydrogen, R is alpha bond between carbon-1 and carbon-2.

3,409,610 29 30 19. A compound according to Formula D of claim 1 21. A compound according to Formula F of claim 1 wherein R is wherein R is OH OH \Q/ 5 H R and R are each hydroxy, R is hydrogen, R is alpha methyl, Y is hydrogen, and R is para-fiuorophenyl.

References Cited R and R are each hydroxy, R is hydrogen, R is alpha methyl and R is para-fluorophenyl.

20. A compound according to Formula E of claim 1 wherein R1 is 10 OH UNITED STATES PATENTS 3,338,928 8/1967 Beard et a1 260397.4 3,364,203 1/1968 Beard et a1. 260239.5

15 R and R are each hydroxy, R is methyl, R is alpha LEWIS GOTTS P'mmry Examiner methyl, and R is para-fluorophenyl. E. G. LOVE, Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE FORMULAS 